16-methylene-17alpha-hydroxy progesterones and derivatives thereof



United States Patent Cfiice 3,359,287 Patented Dec. 19, 1967 3,359,28716-METHYLENE-17u-HYDROXY PROGESTERONES AND DERIVATIVES THEREOF John C.Babcock and J. Allan Campbell, Kalamazoo Township, Kalamazoo County,Mich., assignors to The Upjohn Company, Kalamazoo, Micln, a corporationof Delaware No Drawing. Filed Nov. 16, 1959, Ser. No. 852,981

15 Claims. (Cl. 260-397.4)

This invention relates to novel 16-n1ethylene-17a-hydroxyprogesterones,17-esters thereof, intermediates in the production thereof, and to aprocess for the production thereof, which compounds and process can berepresented by the following formulae:

CH CH3 CH CH3 I o=0 o H CH3 I C 3 L I I on HO HO I II CH CH CH3 CH9 C=O=0 CH CH:

p: 1 cm CH HO- HO IV I III R R CH CH3 :0 =0 CH3 CH3 I Jinn, 1:011,

O: HO-

I V I VI 3,.

(3,17-dlacylate) (17-monoacy1ate) CH CH CH CH3 0 =0 CH8 ---0H --OAc lCHa I CH:

VII I VIII it CH3 CH 5 on, CH

(3:0 0:0 8 I I H3 I O CH CH: 10 I I I IX XI R =0 3 I ]=CH2 VII, VIII O IX CH CH3 E 3 =0 0:: '---o-R' I -OR HO W =CH: 0- CH:

CH I CH I XII I XIII it I';

CH3 C 3 CH3 CH 5:0 '6: --OR -OR HO(, 0H, o= on,

, F F on; aI,"

0: XIV O: XV

wherein R is hydrogen or lower-alkyl, e.g., methyl, ethyl,

propyl, isopropyl, butyl, amyl, octyl, Ac is the acyl radical 7 of ahydrocarbon carboxylic acid, preferably containing from one to twelvecarbons atoms, inclusive, and R is hydrogen or Ac as defined above.

According to this invention, 16-dehydropregnenolone or6-loWer-alkyl-l6-dehydropregnenolone (US. 2,871,- 246) (I) is reactedwith diazomethane to produce the corresponding diazomethane adduct (II).For conven ience in structural representation, the double bond in theadduct portion of the molecule is represented as being between a carbonand a nitrogen atom. However, the double bond may be elsewhere in thering and it is to be understood that II is intended to represent thereaction product of a pregnadienolone (I) and diazomethane. Heatingdecomposes the thus produced diazomethane adduct to produce a16methyl-16-dehydropregnenolone (III) Selective epoxidation of the A-double bond, e.g., with hydrogen peroxide in the presence ofalkali-metal hydroxide, produces a 6a,l7a-epoxy-16 8-methylpregnenolone(IV). Oxidation of the 3fi-hydroxy group of these compounds by anOppenauer oxidation produces the corresponding 16a,l7a epoxy 16Bmethylprogesterone (V) which, when reacted with anhydrous mineral acid,is converted to a l6-methylene-l7a-hydroxypr0gesterone (VII) of thisinvention. The 17-hydroxy-group can then be esterified, e.g., with anacid anhydride in an organic acid and an organic acid catalyst,preferably followed by a mild saponification with an alkali-metalhydroxide in an aqueous alkanol or sometimes preferably with mild acidto remove any 3-enol ester formed and regenerate the 3-keto group, toproduce a l6-methylene-l7u-hydroxyprogesterone l7-acylate (VIII) of thisinvention.

Alternatively, and preferably when R is loweralkyl, the16a,17a-epoxy-16B-methyl compound (IV) can first be reacted withanhydrous mineral acid to produce a 16-methylene-l7a-hydroxypregnenolone (VI). This compound is thendies'terified, e.g., with an acid anhydride in an organic acid catalystwith a strong organic acid such as p-toluenesulfonic acid, to producethe corresponding 3,17-diacetate (VIa). Selective hydrolysis, e.g., withaqueous mineral acid or alkali-metal hydroxide in methanol under mildconditions, produces the corresponding 17-mono acylate (VIb). Thiscompound is then oxidized by an Oppenauer oxidation to produce thecorresponding l6-methylene-l7a-hydroxyprogesterone 17-acylate (VIII).

The l6-methylene-17a-hydroxyprogesterones (VII) and 16 methylene 17ozhydroxyprogesterone 17 acylates (VIII) of this invention are convertedto the unsaturated derivatives thereof of this invention by reactionwith chloranil to produce the corresponding A -compounds (IX), or withselenium dioxide to produce the corresponding A -compounds (X). The A-compounds of this invention (XI) can be prepared by dehydrogenating thecorresponding A -compounds (IX) with selenium dioxide or preferably bydehydrogenating the corresponding A compounds (X) with chloranil.

The 16-methylene-17u-hydroxyprogesterones and 16-methylene-17ot-acyloxyprogesterones of this invention (VII-XI) possesspharmacological activity including progestational, anti-inflammatory,glucocorticoid, and CNS- regulating. The unique combination ofactivities renders these compounds particularly useful in the treatmentof conditions where both progesta'tional and anti-inflammatory activityis desired. The favorable ratio of desired activity to side-effects,e.g., thymic involution and ACTH inhibition, also enhances theusefulness of these compounds.

The compounds of this invention can be administered to the animalorganism, including mammals, in the usual fashion, e.g., topically,orally or parenterally. For this purpose they can be incorporated inpharmaceutical solutions or suspensions, e.g., aqueous solutions orsuspensions for oral or parenteral use, in lotions, ointments, powder,pill or capsule form or oral use.

The novel 16-methylene-17a-hydroxy and 16-methylene-l7u-acyloxycompounds represented by Formulae VII and VIII are also useful asintermediates in the production of the corresponding ll-oxygenatedcompounds (XII-XV). For example, a compound represented by Formula VIIor VIII can be 11,8- or lla-hydroxylated with one of the many species offungi known to oxygenate in that position, e.g., one from the order ofMucorales, Aspergillus, Penicillium, for example, Rhizopus nigricans, orCurvularea lunata, Cunninghamella blakesleeana, to produce a compoundrepresented by Formula XII. Often fungi will remove an ester group. ThusR in the reaction product can be H. If the ester group has been removedin the oxygenation process, it can be replaced in exactly the mannerdescribed in Example 2. A compound represented by Formula XII can beconverted to the corresponding ll-keto compound (XIII) by oxidation,e.g., with chromic acid, chromic anhydride or N-bromoacetamide inpyridine, according to the usual procedures. Alternatively, thell-hydroxy group can be, converted to the 9u-fll101'0-1lf3- hydroxygroup (XIV) by the well known series of reactions involving thedehydration ofthe ll-hydroxy group, e.g., with N-bromoacetamide andanhydrous sulfur dioxide in pyridine or via the p-toluenesulfonateester, to pro duce the corresponding M -compound which is then reactedwith a hypohalous acid, e.g., N-bromoacetamide, N-chlorosuccinimide orN-iodosuccinimide, in the presence of aqueous perchloric acid, toproduce the corresponding 9a-halo-llB-hydroxy compound which is thenreacted with base, e.g., potassium acetate in acetone or sodium orpotassium hydroxide in methanol, to produce the corresponding95,11,9-oxide. Reaction of one of these oxides with anhydrous or aqueoushydrogen fluoride at below room temperature in the usual manner producesa 901,-fillOIO-l1fl-hYdl0XY compound (XIV) which can be oxidized withchromic acid or chromic anhydride to produce the corresponding ll-ketocompound (XV). Compounds XIIXV also possess pharmacological activity,including progestational, anti-inflammatory and glucocorticoid activity,of the same character although of a different order and spectrum thanthe compounds of VII-XI of this invention. They can be administered inthe same manner and forms as described hereinbefore for compoundsVII-XI.

The following preparations and examples are illustrative of the processand products of the present invention, but are not to be construed aslimiting.

PREPARATION 1 16'(17)-diaz0methane adduct 0 6-methyl-16-dehydropregnenolone (II) To a two phase solution of 60 ml. of 50%potassium hydroxide and 200 ml. of ether was slowly added, with stirringand cooling in an ice bath, 22 g. of N-methyl-N-nitroso-N'-nitroguanidine. The resulting ether solution of diazomethanewas decanted and 8.0 g. of 6-methyl-16-dehydropregnenolone (US.2,871,246) was added. The mixture was maintained at room temperatureovernight and the excess diazomethane was decomposed with acetic acidand the solution was washed twice with water, dried over magnesiumsulfate, filtered and then concentrated todryness. The partlycrystalline residue was triturated with acetone, filtered and dried togive 5.5 g. of the 16(17)- diazomethane adduct of6-methyl-l6-dehydropregnenolone, e.g., 6,9 acetyl1,2,3,4,4a,4b,5,6,6a,5fi,7,9a,10,10a, l0b,11-hexahydro 4a,6a,l2trimethylnaphth[2',l 4,5] indano-[1,2-c]pyrazol-2-ol. Recrystallizationof 0.5 g. of this product gives 0.3 g. melting at 184 C. (with evolutionof gas), [a] +21 (CHCl Infrared spectrum analysis indicated that thedouble bond was a C-N double bond. The compound had the correctelemental analysis.

Following the same procedure, IG-dehydropregnenolone is converted to the16(l7)-diazomethane adduct of lo-dehydropregnenolone.

PREPARATION 2 6,16-dimethyl-16-dehydropregnenolone (III) and having thecorrect elemental analysis.

Following the same procedure, the 16(17)-diazomethane adduct of16-dehydropregnenolone is converted to 16-methyl-16-dehydropregnenolone.

PREPARATION 3 6,16,8-dimethyl-1 6a,] 7ot-epoxypregnenolone (IV) To asolution of 1.0 g. of 6,16-dimethyl-16-dehydropregnenolone in 60 ml. ofmethanol was added 1.6 ml. of 5 N sodium hydroxide followed by 4 ml. of30% hydrogen peroxide. The solution was refrigerated overnight and thenmaintained at room temperature for 7 hours. A water soluble precipitateWas removed and the filtrate was concentrated in a rotary vacuumevaporator nearly to dryness. Water was added and the product collectedon a filter, washed with water and dried to give 1.0 g. of6,16B-dimethyl-l6a,l7a epoxypregnenolone melting at 155158 C.Recrystallization from aqueous methanol raised the melting point tol62164 C., [ab-17 (CHCl The elemental analysis was correct.

Following the same procedure, 16-methyl-l6-dehydropregnenolone isconverted to l6,8-methyl-16a,17a-epoxypregnenolone, melting at 189l93 C.

PREPARATION 4 1 6 fl-m ethyl-J 6 e,1 7 ot-epoxyprogesterone (V) Asolution of 5.0 g. of 16,6-methyl 160:,17oc epoxypregnenolone in ml. ofcyclohexanone and 35 ml. of toluene was boiled a few minutes to removeany traces of water and then 2.5 g. of aluminum isopropoxide was added.The solution was stirred under reflux for 35 minutes, cooled, dilutedwith a little methylene chloride and then Washed with dilute sodiumhydroxide, salt water, dilute hydrochloric acid, and then twice withsalt water. The solution was dried and then chromatographed on 200 g. ofmagnesium silicate (Florisil). The l6fl-methyl-16a,l7a-epoxyprogesterone was eluted with hexanes (Skellysolve B) plus68% acetone and then recrystallized from a mixture of hexanes andacetone to give 2.9 g. of crystals thereof melting at 162-164 C.,[uh-152 3),

EtOH m...

240 my, a =17,4OO

An additional 0.65 g. of the same product melting at 15 1 161 C. wasobtained from the mother liquor.

Following the same procedure, 6,16B-dimethyl-16oz,170t-6POXYPI6gI16I101OI1C is oxidized to 6a,l6fl-dimethyl-16a,17a-epoxyprogesterone.

PREPARATION 5 I 6-methylen e-I 7a-hydr0xypregnen0l0ne (VI)dimethylglutaric, adipic, pimelic,

8 from methanol to give 0.5 g. of 16-methylene-17ahydroxypregnenolonemelting at 251-255" C., [a] 164 (CHCl and having the correct elementalanalysis.

Following the same procedure BB-hydroxy6,16B-dimethyl-16a,17a-epoXy-S-pregnen-ZO-one is converted to 6-methyl-16-methylene-17a-hydroxypregnenolone.

EXAMPLE 1 16-methylene-17ot-hydroxyprogesterone To a solution of 2.0 g.of l6fl-methyl-l6-u,17a-epoxyprogesterone in ml. of absolute ether wasadded dropwise 1.0 ml. of 32% hydrogen bromide in acetic acid. Thesolution was stored in the refrigerator for several hours. The crystalswere collected, washed with ether, slurrier with dilute aqueous sodiumbicarbonate, washed with water and dried to give 1.9 g. of16-methylene-l7ahydroxyprogesterone melting at 212-228 C. (dec.), din-(CHCIS),

ECOH maz- 241 my, a =17,600 Nuclear magnetic resonance established thepresence of the isolated exocyclic double bond.

Following the same procedure, 6u,l6,8-dimethy1*16a,17u-epoxyprogesterone is converted to 6a-methyl-16-methylene-17a-hydroxyprogesterone.

EXAMPLE 2 I 1 6-methylene-J 7a-hydr0xypr0gesterone 1 7-Zzcetaze Nitrogenwas bubbled through a solution of 1.95 g. of16-methylene-17u-hydroxyprogesterone in 32 ml. of acetic acid and 8 ml.of acetic anhydride and 0.8 g. of p-toluenesulfonic acid was then added.The solution was stirred for 2 hours at room temperature and then pouredinto a mixture of ice and water. The thus-produced16-methylene-l7a-hydroxyprogesterone 3-enol acetate l7-acetatesolidified upon the addition of a small amount of ether. The precipitatewas separated, Washed with water and dried. It was then dissolved in 20ml. of warm methanol and 2 ml. of 10% sodium hydroxide was added. Thesolution was chilled almost immediately and the product flooded out withwater. The precipitated product was chromatographed on acid washedalumina. Hexanes (Skellyslove B) plus 6-7% acetone eluted 0.6 g. of 16-methylene-17u-hydroxyprogesterone 17-acetate melting at 227-230 C., [a]52 (CHCl A 240 mu, a =17,550

Following the same procedure,6ot-II16thYl-16-I1'l6thylene-17a-hydroxyprogesterone is converted toa-methyl- 16-methylene-l7a-hydroxyprogesterone 17-acetate.

Similarly, 16-methylene-l7ot-hydroxyprogesterone and6ot-methyl-l6-methylene 17cc hydroxyprogesterone are converted to otherl7-acylates thereof by esterification of the l7-hydroxy group, e.g., byreaction with the appropriate acid anhydride or acid in the presence ofan esterification catalyst, etc. Examples of 16-methylene-17ahydroxyprogesterone 17-acylates and6a-methyl-l6-methylene-l7a-hydroxyprogesterone 17-acylates preparedinclude those wherein the acyl group is the acyl radical of ahydrocarbon carboxylic acid, for example, a lower-aliphatic acid, e.g.,formic, propionic, butyric, isobutyric', valeric, isovaleric,trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic,diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric, acyclic acid, e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g.,cyclopentylformic, cyclopentylacetic, fl-cyclopentylpropionic,cyclohexylformic, cyclohexylacetic, ,B-cyclohexylproyionic, an aryl oralkaryl acid, e.g., benzoic, methylbenzoic, dimethylbenzoic,ethylbenzoic, 2,4,6 trimethybenzoic, 2,4,6-triethylbenzoic, a-naphthoic,3-methyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic,phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid, (whichcan be converted to water soluble, e.g., sodium, salts) e.g., succinic,glutaric, a-methylglutaric, S-methylglutaric, 54%

and suberic acid.

EXAMPLE 3 1 6-121 ethyl ene-l 7u-lzya'r0xy-1 ,4-pregnadiene-3,20-dion e17-acetate A mixture of 100 mg. of 16-methylene-17a-hydroxyprogesterone17-acetate dissolved in 6 ml. of tertiary butyl alcohol and 0.55 ml. ofacetic acid was heated together with 30 mg. of selenium dioxide toapproximately 75 C. under stirring for about 24 hours. Thereafter,another 30 mg. portion of selenium dioxide was added and the mixtureheated to 75 C. under continuous stirring for another 24 hours. Themixture was then cooled, filtered to remove the selenium dioxide andevaporated. The residue was dissolved in methylene chloride and washedwith freshly prepared ammonium sulfide, ammonium hydroxide and water.After removal of the solvent the residue was recrystallized from amixture of hexanes and acetone to give16-methylene-l7a-hydroxy-l,4-pregnadiene-3,20- dione l7-acetate. Furtherpurification can be achieved by chromatography over magnesium silicateeluted with hexanes containing increasing proportions of acetone.

Following the procedure of Example 3, 6a-methyl-16-methylene-17a-hydroxyprogesterone 17-acetate,6tx-methyl-16-methylene-17a-hydroxyprogesterone, and16-methylene-17u-hydroxyprogesterone are converted toGot-methyl-16-methylene-17a-hydroxy-1,4-pregnadiene 3,20-dione17-acetate, 6a-methyl-l6-methylene 17a hydroxy1,4-pregnadiene-3,20-dione, and 16-methylene-17a-hydroxy-1,4-pregnadiene-3,20-dione, respectively. Other 17-acylate esters of theabove-described starting 17-hydroxy compounds, e.g., wherein the acylradical of the acylate group is that of an acid named in the paragraphfollowing Example 2, are dehydrogenated to the corresponding 1-dehydrocompounds.

EXAMPLE 4 1 6-metIzylene-1 7a-hydr0xy-4,6-pregnadiene-3,2 O-dione 1 7acetate 400 mg. of 1G-methylene-17a-hydroxyprogesterone 17- acetate, 600mg. of recrystallized 2,3,5,6-tetrachloro-1,4- benzoquinone (chloranil)and 24 ml. of tertiary amyl alcohol was heated to boiling under nitrogenwith a few boiling chips, and gently refluxed for 6 hours. The mixturewas cooled and evaporated to dryness under reduced pressure. The solidresidue (with exception of some chloranil, which is insoluble) wasdissolved in about 100 ml. of ether and filtered. The chloranil on thefilter paper was washed with several portions of ether and the combinedether filtrates were washed with two 200-ml. portions of cold 2% sodiumhydroxide. The ether filtrates were washed with cold water until thewashings were neutral, then with saturated sodium chloride solution. Thepooled ether solutions were dried over sodium sulfate and evaporated todryness. The residue was crystallized from a mixture of hexanes andacetone to give 16-II16thYlEn6-17oahydroxy-4,6-pregnadiene-3,ZO-dione17-acetate.

Following the procedure of Example 4,

a-methyl-lfi-methylene-17a-hydroxyp1'ogesterone 17-acetate,

6a-methyl-1G-methylene-17u-hydroxyprogesterone, 16-

methylene-17a-hydroxyprogesterone,

16-methylene-17a-hydroxy-1,4-pregnadiene 3,ZO-dione,

6a-methy1ene-17u-hydroxy-1,4-pregnadiene-3,20-dione,

6a-methyl-l 6-methylene-17u-hydroxy-1,4-pregnadiene- 3,20-dione17-acetate, and

16-methylene-17ot-hydroxy-1,4-pregnadiene-3,20-dione 17-acetate areconverted to 6-methyl-16-methylene-17u-hydroxy-4,6-pregnadiene-3,20-dione 17-acetate,6-methyl-16-methylene-17et-hydroxy-4,6-pregnadiene- 3 ,20-dione,l6-methylene-17ot-hydroxy-4,6pregnadiene-3,20-dione,

8 16-methylene-17et-hydr0xy-1,4,6-pregnatriene-3,20-dione,6-methyl-l6-methylene-17a-hydroxy-1,4,6-pregnatriene- 3,20-dione,6-methyl-16-methylene-17a-hydroxy-1,4,6-pregnatriene- 3,20dione17-acetate, and 16-methylene-17u-hydroxy-1,4,6-pregnatriene-3,20-dione17-acetate,

respectively. Other 17-acylate esters of the above-described starting17-hydroxy compounds, e.g., wherein the acyl radical of the acylategroup is that of an acid named in the paragraph following Example 2, aredehydrogenated to the corresponding 6-dehydro compounds.

EXAMPLE 5 6-methyl-1 6-methylene-1 7u-hydroxyprogesterone 1 7-acefateFollowing the procedure of Example 2, 6-methyl-16-methylene-17a-hydroxypregnenolone is convertedd to 6-methyl-16-methylene-17ix hydroxypregnenolone 3,17-diacetate. Thecompound is then selectively hydrolyzed with about 4 molar equivalentsof concentrated hydrochloric acid in refluxing methanol for one hour,e.g., in the manner of the copending application of Babcock et al., S.N.740,553, Preparation 113, to produce6-methyl-16-methylene-l7a-hydroxypregnenolone 17-acetate. Oxidation ofthis compound according to the procedure of Preparation 4 gave6ot-methyl-16-methylene-l7a-hydroxyprogesterone 17-acetate.

Similarly, 16-methylene 17m hydroxypregnenolone is converted, via its3,17-diacetate and its 17-mono acetate to16-methylene-17a-hydroxypr0gesterone 17-acetate.

Similarly, other 3,17-diacylates and l7-monoacylates of the abovedescribed compounds are prepared by substituting another acid anhydride,e.g., wherein the acyl radical is that of an acid named in the paragraphfollowing Example 2, for the acetic anhydride employed in the finalstep.

1 1 5,1 7ot-dihydr0xy-1 6-methyleneprogesterone Five sterile Erlenmeyerflasks containing m1. of a medium consisting of 1 g. commercial dextroseand 1.2 g. corn steep liquor solids adjusted to a pH of 5.0 wereinoculated with spores from a malt extract agar culture of Curvularialunata, American Type Culture Collection No. 12,017. After 72 hoursthese flasks were used to inoculate 10 liters of the same medium in astirred and baffled fermenter. 10 ml. of sterile lard oil was used as anantifoaming agent. An air fiow of 0.5 liter per minute was maintainedfor 48 hours with a fermenter temperature of 28 C. At this time the pHwas 7.2. Two g. of 16-methylene-17a-hydroxyprogesterone dissolved in 30ml. of dimethylformamide was then added to the fermenter. Fermentationwas continued for another 48 hours and the contents of the fermenter wasthen filtered through gauze. The mycelial solids were washed with waterwhich was then combined with the filtered beer. The steroids wererecovered from the beer by extracting 4 times with a mixture of 3 partsof methylene chloride and 1 part of ethyl acetate, The partlycrystalline extractives were triturated with a mixture of ether andethyl acetate to give 0.55 g. of11B,l7ix-dihydroxy-16-'nethyleneprogester0ne. Recrystallization of thisproduct, with activated charcoal treatment, from ethyl acetate gavecrystals thereof melting at 206-213 C.,

EtOH mu.

241 my, a 16,150

Recrystallization from ethyl acetate raised the melting point to 212-215C., [@1 -28 (CHCl 9a-flu0r0-11B, I 7a-dihydroxy-16-methylene-4-pragnene-3,20-di0ne and sulfur dioxide gas is passed over the surfacewhile the mixture is shaken until the solution gives no color withacidified starch-iodine paper. During the addition of sulfur dioxide gasthe reaction mixture becomes warm. The temperature is kept under 30 C byexternal cooling and by varying the rate of sulfur dioxide addition.After standing at room temperature for a period of 15 minutes, thereaction mixture is poured into ice water and the resulting precipitateextracted with ether. The ether extract is washed with hydrochloric acidand water, and evaporated to dryness. This material is recrystallizedfrom a mixture of acetone and hexanes to give16-methylene-17uhydroxy-4,9 1 1 -pregnadiene-3,20-dione. I

To a solution of 300 mg. of l6-methylene-17a-hydroxy- 4,9(11)pregnadiene 3,20 dione in a 1:2 mixture of methylene chloride andtertiary butyl alcohol is added a solution of 1.0 ml. of 72% perchloricacid in water followed by a solution of 150 mg. of N-bromo-acetamide in2.5 ml. of tertiary butyl alcohol. After stirring the reaction mixtureto homogeneity, a solution of 150 mg. of sodium sulfite in ml. of wateris added and the reaction mixture is concentrated to a small volumeunder reduced pressure at about 60 C. The concentrate is cooled in anice bath while stirring and water is added. After stirring for severalminutes, the crystalline product is isolated by filtration, the solid isWashed with water and air-dried to give 90: bromo 11,8,17a dihydroxy 16methylene 4- pregnene-3,20-dione.

Alternatively, if desired, the concentrate is cooled, diluted withwater, extracted with methylene chloride, washed, dried and themethylene chloride solution chromatographed to give substantially pure9a-bromo-l 1 3,170- dihydroxy-16-methylene-4-pregnene-3,ZO-dione.

To a solution of 400 mg. of 90: bromo 11,8,17udihydroxy-16-methylene-4-pregnene-3,20-dione is acetone is added 400 mg.of potassium acetate and the resulting suspension is heated under refluxfor a period of 18 hours. The mixture is then concentrated to a smallvolume on the steam bath and water is then added. The potassium acetategoes into solution and the steroidal product separates out. Theprecipitated steroid is separated by filtration and recrystallized froma mixture of acetone and hexanes to give 95,1lfl-epoxy-l6-methylene-17a-hydroxy-4-pregnene- 3,20-dione.

To a solution of 250 mg. of 9,8,11B-epoxy-l6-methylene-17a-hydroxy-4-pregnene-3,20-dione in 5 ml. of methylene chloride isadded about 1 ml. of a 48% solution of hydrogen fluoride. The two-phasemixture is stirred, then diluted with methylene chloride and carefullypoured into water containing sodium bicarbonate. After shaking toneutralize the excess hydrogen fluoride, the methylene chloride isseparated and the water phase is extracted with more methylene chloride.The combined methylene chloride solution is dried over anhydrous sodiumsulfate, diluted with ether and chromatographed over a column ofmagnesium silicate. The column is eluted with hexanes containingincreasing proportions of acetone to give 901- fluoro 115,175 dihydroxy1'6 methylene 4 pregnene-3,20-dione.

Esterification of 16-methylene-17a-hydroxy-4,9(11)-pregnadiene-3,20-dione in the manner described in Example 3 produces16-methylene-17a-hydroxy-4,9(11)- pregnadiene-3,20-dione 17-acetatewhich is converted in the subsequent steps described above to9u-fluoro-11/3, 17a dihydroxy 16 methylene 4 pregnene 3,2 0- dione17-acetate.

Following the same procedure 6a-methyl-16-methylene- 17ahydroxyprogesterone 17 acetate is converted to 6mmethyl 9a fluoro11,8,170t dihydroxy 16 methylene-progesterone 17-acetate.

We claim:

1. 16 methylene 17a hydroxy 1,4 pregnadiene- 3,20-dione l7-acetate.

. l0 2. Compounds represented by the fo'rmulat E o=o' hydroxy 4,6pregnadienejam wherein R is selected from the group consisting ofhydrogen and lower-alkyl and R is selected from the group consisting ofhydrogen and the acyl radical of a hydrocarbon carboxylic acidcontaining from 1 to 12 carbon atoms, inclusive.

6. 16 methylene 17a hydroxy 1,4,6 pregnadiene- 3,20-dione 17-acetate.

7. 6 methyl 16 methylene 17a hydroxy 1,4,6- pregnatriene-3,20-dione17-acetate.

8. A compound of the formula:

9. 17a acyloxy 6 methyl 16 methylene pregna- 4,6-diene-3,20-dioneshaving the general formula 1 1 where R is an acyl group of a hydrocarboncarboxylic acid containing up to 6 carbon atoms. 10. A compound of theformula =0 0 I Di -CH:

dihydroxy 16 methylene- 12 15. A compound of the formula:

jam of wherein R is selected from the group consisting of hydrogen andthe acyl radical of a hydrocarbon carboxylic acid containing from 1 to12 carbon atoms.

References Cited UNITED STATES PATENTS 2,837,464 6/1958 Nobile 260-397E. L. ROBERTS, Primary Examiner. I FROME, L. GOTTS, L. H. GASTON, M.LIEBMAN,

Examiners.

2. COMPOUNDS REPRESENTED BY THE FORMULA